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ATP plays large role in spinal cord injury

ATP plays large role in spinal cord injury
By Brad Amburn
United Press International
Published 8/3/2004 1:42 PM

WASHINGTON, Aug. 3 (UPI) -- Adenosine triphosphate, which provides energy for the body's cells, plays a major role in spinal cord injuries by killing motor neurons surrounding the injury site -- a discovery that could lead to new and much-needed treatments to prevent paralysis, researchers told United Press International.

Doctors at the University of Rochester Medical Center were surprised to find that cells called astrocytes -- which provide nutrients and remove wastes in the brain and spinal cord -- release high amounts of ATP in the tissue surrounding spinal cord injury sites. ATP then binds to motor neurons and kills them, said Dr. Maiken Nedergaard, a professor of neurosurgery and the study's lead researcher.

"This study is different fundamentally from other studies on spinal cord injury because we are not going in and regenerating tissue -- we are going in and saving tissue," Nedergaard told UPI. She said prior research has focused on regenerating tissue after injury by injecting stem cells or promoting the growth of nerve fibers.

In the new study, the researchers were able to develop a drug for rats with spinal cord injuries that prevented ATP from binding to spinal nerve cells, thereby allowing the rats to make almost a complete recovery within six weeks after injury and treatment, Nedergaard said.

After a spinal cord injury, the nerve cells in and around the injury site quickly begin to die, with the dead tissue area expanding three to four times larger than the initial injury site within two days.

Today, steroids such as methylprednisolone compose the only available treatment for spinal cord injuries, but they improve recovery by only about 20 percent, said Dr. Wise Young, a research professor at Rutgers University who pioneered the use of steroids to treat such injuries.

"In spinal cord injury, it has been known for the past 100 years that nerve cells around the injury site quiet down, so it's regarded (that) tissue just gets silent and nothing happens," Nedergaard said. "But we used new techniques to study the support cells and we got a big surprise because the support cells, instead of being quiet, were extremely active and this was completely unexpected."

Most spinal injury research in the past has focused on the motor neurons, because they are the most vital to movement, Nedergaard said. Her research team decided to focus on the astrocytes and their "housekeeping role," because in stressful situations, such as spinal cord injuries, it is important to understand how these cells work to maintain a healthy environment, she explained.

The team found that hyperactivity by the astrocytes led to the release of ATP levels up to hundreds of times higher than normal, she said. ATP is harmful when released in high amounts because it binds to the "death receptors" of nerve cells and kills them.

This process seems to be the reason much of the damage in spinal cord injuries occurs after the accident, resulting in patients continuing to lose function for up to a week, and leaving doctors with no effective treatment to stop the resulting paralysis.

"Secondary injury is a big issue and it's very unfortunate because patients are in the hospital bed when this occurs and doctors just don't know how to treat it," Nedergaard said.

Secondary injury also is very damaging due to the swelling of cells around the injury site. Because the brain and spinal cord are confined with the skull and vertebrae, any type of swelling restricts blood supply, so neurons do not receive the oxygen or glucose they need to function properly.

Nedergaard said by focusing on saving existing tissue before much of the secondary injury occurs, doctors could help patients leave the hospital earlier and suffer less severe aftereffects.

The treatment requires the ATP inhibitor to be administered within a few hours after the injury, something Nedergaard said should be doable, because most spinal cord injury patients are sent to the hospital immediately.

If approved drugs used to treat other diseases can be screened for their inhibitory effects on ATP release, Nedergaard said, then a treatment could be clinically available within five years. If new drugs must be developed, however, the process could take longer, because they would have to be tested for their ability to move through the blood-brain barrier to reach the astrocytes, she added.

Naomi Kleitman, a program director at the National Institute of Neurological Disorders and Stroke in Bethesda, Md., who specializes in spinal cord injury, called the finding interesting, but questioned its value because of the short window of opportunity for treating patients.

"The researchers applied the inhibitor to rats one hour after injury, but even then, it could not give EMTs and physicians enough time to get there and deliver treatment," she told UPI.

Although heightened levels of ATP seem to cause damage to tissue surrounding the injury, the lack of ATP at the injury site also is a problem because it also is linked to nerve cell damage and death, Kleitman said.

"Secondary damage is a very complicated process," she said, "and scientists are trying to understand all the complicated chemical processes going on that damage the nervous system but are also working on how to save the beneficial ones. Much more work would need to be done to prove how clinically relevant this would prove to be."

Young, who has been working the past six years on how to regenerate the spinal cord after injury, also said this is an important study, but acknowledged that it raises questions.

Nevertheless, he remains optimistic.

"I think this is an important mechanism that is changing the way we're thinking about tissue damage in spinal cord injury," Young said. "I think eventually there will be therapies that will be practical to treat other acute spinal cord injuries, including stroke and other damage to the central nervous system."

Young said he will be working with researchers from Rochester to test potential treatments in the near future.

Marci Roth, executive director of the National Spinal Cord Injury Association, said the finding is very exciting in terms of treating people who first sustain injury, but she added it is important to remember that 100,000 people currently are living with spinal cord injuries.

"As we make this kind of progress, we also need to be working aggressively in the kinds of research in how people with spinal cord injury can maximize their function," Roth told UPI. "We need to make sure research is well-supported that helps improve the quality of life for those with paralysis from spinal cord injuries."